No abstract

The syntheses of bis(triazolium)carbazole precursors and their corresponding coinage metal (Au, Ag) complexes are reported. For alkylated triazolium salts, di‐ or tetranuclear complexes with bridging ligands were isolated, while the bis(aryl) analogue afforded a bis(carbene) AuI‐CNC pincer complex suitable for oxidation to the redox‐stable [AuIII(CNC)Cl]+ cation. Although the ligand salt and the [AuIII(CNC)Cl]+ complex were both notably cytotoxic toward the breast cancer cell line MDA‐MB‐231, the AuIII complex was somewhat more selective. Electrophoresis, viscometry, UV‐vis, CD and LD spectroscopy suggest the cytotoxic [AuIII(CNC)Cl]+ complex behaves as a partial DNA intercalator. In silico screening indicated that the [AuIII(CNC)Cl]+ complex can target DNA three‐way junctions with good specificity, several other regular B‐DNA forms, and Z‐DNA. Multiple hydrophobic π‐type interactions involving T and A bases appear to be important for B‐form DNA binding, while phosphate O⋅⋅⋅Au interactions evidently underpin Z‐DNA binding. The CNC ligand effectively stabilizes the AuIII ion, preventing reduction in the presence of glutathione. Both the redox stability and DNA affinity of the hit compound might be key factors underpinning its cytotoxicity in vitro.

No abstract

Alzheimer’s disease is the most common neurodegenerative disease and currently poses a significant socioeconomic problem. This study describes the uses of computer-aided drug discovery techniques to identify novel inhibitors of acetylcholinesterase, a target for Alzheimer’s disease. High-throughput virtual screening was employed to predict potential inhibitors of acetylcholinesterase. Validation of enrichment was performed with the DUD-E data set, showing that an ensemble of binding pocket conformations is critical when a diverse set of ligands are being screened. A total of 720 compounds were submitted for in vitro screening, which led to 25 hits being identified with IC50 values of less than 50 μM. The majority of these hits belonged to two scaffolds: 1-ethyl-3-methoxy-3-methylpyrrolidine and 1H-pyrrolo­[3,2-c]­pyridin-6-amine both of which are noted to be promising compounds for further optimization. As various possible binding poses were suggested from molecular docking, molecular dynamics simulations were employed to validate the poses. In the case of the most active compounds identified, a critical, stable water bridge formed deep within the binding pocket was identified potentially explaining in part the lack of activity for subsets of compounds that are not able to form this water bridge.